4-hydroxyethyl-biphenylyl-butadienols

ABSTRACT

4-Hydroxyethyl-biphenylyl-butadienols e.g., 2-(4&#39;&#39;-(1hydroxyethyl)-biphenylyl)-3,4-pentadien-2-ol, and their preparation are described. The compounds are useful as antiinflammatories.

United States Patent 1 Anderson 1 June 10, 1975 I 4-HYDROXYETHYL-BIPHENYLYL- BUTADIENOLS [75] Inventor: Paul L. Anderson, Dover, NJ.

[73] Assignee: Sandoz, lnc., E. Hanover, NJ.

[22] Filed: Dec. 28, 1973 [21] Appl. No.: 429,388

[52] US. Cl... 260/618 R; 260/239 B; 260/247.7 A; 260/268; 260/293.53; 260/326; 260/87;

2611/3451; 260/446.1 R; 260/503; 260/512 R; 260/543 R; 260/567.6 M; 260/618 D; 424/343 3,267,l45 8/1966 Land et a1 2601618 R FOREIGN PATENTS OR APPLICATIONS 2,258,349 9/1973 Germany 260/618 R OTHER PUBLICATIONS Gelen et 211., Chemical Abstracts, Vol. 77, Abstract No. 113707 U (1972).

Primary ExaminerDona1d G. Daus Assistant ExaminerDavid B. Springer Attorney, Agent, or Firm-Gerald D. Sharkin; Richard E. Vila; Frederick H. Weinfeldt [57] ABSTRACT 4-Hydroxyethyl-biphenyIyI-butaclienols e.g., 2-[4'-(1- hydroxyethyl)-biphenylyl]-3,4-pentadien-2-o1, and their preparation are described. The compounds are useful as anti-inflammatories.

2 Claims, N0 Drawings OH OH I l CH3CH.\ .tr- Cll=C==-Cll wherein R is a hydrogen atom. methyl or ethyl. preferably methyl.

(ompounds l are obtainable by reducing with a complex metal hydride. a conesponding alkynol compound of the l'ormula ll. (process a):

on t

II Acc-Ec-cii r.

wherein R is as delined above; and A is A OH v- 18 CH IH and IV is either (at a quaternary ammonium radical; (b) an ether selected lrom the group consisting of tetrahydrol'uran 3 ylosy; tetiahydropyran'2 ylo\y or 4 methosy tetrahydrtipyran-lyloxy; (c) halo having an atomic weight ol from about I) to L17. e.g., lluoro, chloro, hromo. or iodo; or (d) a sul l'onylosy radical The complex hydride reducing agents may be ol the lormuIa llla or "lb:

7 z I l M Q 2 'r H 1115, or 'I' ii 111%) l l Z3 2 wherein 'l' is aluminum. gallium or boron, and

7., If and I," are. independently. a hydrogen atom.

alkvl of l to h carbon atoms, alkoxv oll to o ear hon atoms; or alkoxyalkosy having from I to (i total carbon atoms;

l and 79" are. independently. hydrogen or alkyl ol l to h carbon atoms. and

M is an alkali or alkaline earth metal. such as lithium.

sodium. potassium. calcium or magnesium,

lsemplary olsueh complex hydrides are lithium alumi num hydride. sodium dihydrobis (Z-methoxyethoxyl aluminate. sodium diethyl aluminum dihydride. lithium borohydride, lithium gallium hydride. magnesium alumimnn hydride. lithium diisobutylmethyl aluminum hy dride. lithium trimethosy aluminum hydride. diethyl aluminum hydride and dihorane. preferably lithium aluminum hydride or sodium dihydrohis (2- l\lL.lll(l\)'LlllU\ \'l alunnnatev 'l he complex hydrides (Illa and lllhl are either known and may be prepared by methods described in the literature or Where not known may be prepared by methods analogous to those for preparing the known compounds Many ol the complex hydrides are com mercially available lroeess (a) should be carried out in a medium which is not detrimental to the reaction. such as in an aprotic organic solvent, e.g.. an ether such as diethyl ether. tetrahydroluran or diosane. an aromatic medium. such as hen/cue. toluene or pyridine or a saturated aliphatic hydrocarbon. such as pentane. hexane or octane. The medium may he a mixture or ingle material The reaction may. for example. be carried out at about 4"" to 30 lZtl"(' eg. at the boiling point ol the medium However; temperatures ol l rom about It) to l5ll"(' are preferred. While the higher temperatures result in a ltlSlLl reaction rate. reactions carried out at loner temperatures tend to gi\e purer products lhe reaction product (a ('ompound I) may be recovered by conventional means. eg. by carefully adding a small amount of water or aqueous solution. e.g.. aqueous ammonium chloride. or sodium hydro\ide to the reaction mi\ture liltcring ol'l' the inorganic byproducts oi hydrolysis products ol'the hydride ion source. and then separating the ('ompound l product from the organic phase by i such mcans as precipitation. e\traction. crystalli/ation.

Jll

till

chnmiatography or liquid liquid e\traction As will he armreciateil by those skilled in the art. it is prcl erred to e\eludc moisture from the reaction. cg. by rise ol' anhydrous solvents and conditions. The reaction may be advantageously carried out in an inert atmosphere. erg. under nitrogen gas.

l'he compounds of formula ll in which I. is a quarternary ammonium radical are compounds ol l'ormula llu:

Ila

wherein A and R are as defined above; and l. is the radical.

wherein R and R independently represent alkyl having I to 4 carbon atoms. unsubstituted cycloalkyl having 5 to o ring carbon ic. cyclopentyl or cyelohexyl; or together, with N, represent a heterocyclic ring hav ing R to 7 members selected from the group eonsisting of unsubstituted pyrrolidino. Pipcridino. homopiperidino, morpholino. and their alkyl sub stituted derivatives containing from l to 3 alkyl groups of l to 4 carbon atoms;

R represents alkyl having l to 4 carbon atoms. e.g.. methyl. ethyl. propyl or butyl including isomeric forms where they exist. although the unbranched alkyls are preferred. especially methyl. and

X is an anion derived from a mineral acid or an organic sulfonic acid. provided that X is not fluoro. e.g.. iodo or methylsulfonyl.

Compounds llu can be prepared by quaternizing a compound of the formula V:

A. R. R and R are as defined above. with a com pound of the formula \*l:

R and X are as defined above The quaternization can be carried out in the conventional manner. cg, in a suitable solvent such as ace tone. at a temperature of from "20 to +3tlC.. neither the solvent nor the temperature being critical. A preferred compound V1 is methyl iodide. The compounds of formula \"l are known per se or can be prepared from known materials by conventional methods. and many are commercially available.

The compounds of formula ll in which L is an ether moiety. i.e.. the compounds of formula llb:

wherein A and R are as defined above. and L" is tetrahydrofuran-Z-yloxy. tetrahydropyran-2- yloxy or 4-methoxy-tetrahydropyran-4-yloxy can be prepared by reacting a compound of the formula Vll VII The compounds of formula II in which L is halo other than iodo. i.e.. those compounds of formula llc:

it) \vherein A and R are as defined above. and L is fluoro. chloro or bromo can be prepared by reacting a compound of the formula 1X:

OH l ACCEC-CH --OH IX l wherein A and R are as defined above with the appropriate halide selected from the group of thionyl chloride or bromide. phosphorus pentachloride or bromide and hydrocarbon sulfonyl fluorides. e.g.. benzyl sulfonyl fluoride. tosyl fluoride and mesyl fluoride. in an organic medium such as hexane. benzene or dimethoxyglycol. For the chlorination and bromination a tertiary amine base. such as pyridine. is included in the reaction mixture and the reaction temperature is about 0 to 20C. For the fluorination the reaction temperature is 0 to about 150C.

Compounds of formula ll in which L is iodo are conveniently prepared by reacting corresponding compounds of formula llc in which L"' is chloro. with sodium iodide in acetone. the reaction being carried out in conventional manner for replacing a chloro with an iodo.

The compounds of formula ll in which L is a sulfonyloxy radical are compounds of formula Ild:

( wherein A and R are as defined above. and

L" is a sulfonyloxy radical which may be either alkylsulfonyloxy in which the alkyl group may be substituted. e.g.. halo. or unsubstituted and contain front 1 to as many as lb or more. preferably l to 6 carbon atoms. e.g.. methane sultonyloxy. ethanesulfonyloxy. 3chloropropanesulfonyloxy. or lhexadecanesulfonyloxy; or arylsulfonyloxy in which the aryl group is phenyl. naphthyl or substituted phenyl. which may have from l to 3 substituents independently selected from the group con sisting of alkyl of l to 6 carbon atoms. alkoxy of l to 6 carbon atoms. halo and nitro.

g Compounds lld can be prepared by reacting a compound of the formula IX above with an appropriate alkylsulfonyl chloride. such as methanesulfonyl chloride. 3-chloropropanesulfonyl chloride or 1- wherein R and R are as defined above. This reaction may be carried out at temperatures of to 50C.. conveniently at room temperature. and in the presence of an organic solvent such as tetrahydrofuran. The compounds of formula XI are known or can be produced in known manner by reacting a compound of the formula XIV:

ME C-CH2-N XIV wherein R and R are as defined above. with lithium metal at a temperature of 0 to 50C. in a suitable solvent such as ethylene diamine. The compounds of formula V can also be prepared by a process (b) which involves reacting a compound of formula XII:

I A---CCECII XII wherein A and R are as defined above. with a compound of formula XIII:

a0 c11 N x111 wherein R' and R are as defined above.

In process (h). a compound of formula XII is reacted with a compound of formula XIII at a temperature of to 50C. preferably at room temperature. in the presence of an inert solvent. and in the presence of mono-valent coinage metal ion. e.g.. copper ion. as catalyst. preferably cuprous chloride or cuprous oxide. al-

though salts and the like of other coinage metals. i.e.. silver and gold (I). can likewise be used. The compounds of formula XII can be prepared by reacting a compound of formula VII above in a solvent such as dimcthylacetamide or dimethylsulfoxidc with a suitable acetylene reagent. such as sodium or lithium acetylide conveniently at room temperature.

The compounds offormulae XIII and XIV used in the above-identified preparations of Compounds V are known or can be produced from known materials by conventional techniques. and many are commercially available.

Alternatively. in preparing the Compound I in which R is methyl. in place of a Compound II (which bears at the 4'-position a l-hydroxyethyl function) there may conveniently be used an 4-acetyl analog thereof. i.e.. a Compound II. Compounds II are obtainable in the same manner as described herein for the preparation of Compounds 11. using appropriate 4-acetyl-bearing starting materials. which are known or obtainable in the same manner as starting materials for Compounds 11. e.g.. 4.4-diacetyl biphenyl as Compounds VIIv Under the reducing conditions of process a). the 4" acetyl function of a Compound II will be reduced to a l-hydroxyethyl function. hence. yielding the same Compound I as would be obtained from a Compound II in which R is methyl.

The compounds of formula ([1 are useful because they possess pharmacological activity in animals. In particular. the compounds (1] are useful as antiinflammatory agents as indicated by the Carragecnan induced edema test on rats (oral administration at 1 to 200 mg/kg). For such use. the compounds may be conr bined with a pharmaceutically acceptable carrier. and such other conventional adjuvants as may be necessary. and administered orally in such forms as tablets and capsules. clixirs. suspensions and the like or parenterally in the form ofan injcctable solution or suspension. The dosage administered will. of course. vary depending upon the compounds used and the mode of administration. However. in general. satisfactory results are obtained when administered at a daily dosage of from about I milligram to about 250 milligrams per kilogram. e.g.. from about 1 milligram to about 175 milligrams per kilogram of body weight. preferably given in divided doses 2 to 4 times a day. or in sustained release form. For most mammals. the administration of from about milligrams to about 3.000 milligrams. e.g.. front about milligrams to about 2.000 milligrams. of the compound per day provides satisfactory results and dosage forms suitable for internal administration comprise from about 25 milligrams to about 1.500 mil Iigrams. e.g.. from about 40 milligrams to about 1.000 milligrams. of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

For the above usage. oral administration with carriers may take place in such conventional forms as tablets. dispersible powders. granules. capsules. syrups and elixirsv Such compositions may be prepared according to any method known in the art for manufacture or pharmaceutical compositions. and such compositions may contain one or more conventional adjuvants. such as sweetening agents. flavoring agents. coloring agents and preserving agents. in order to provide an elegant and palatable preparation. Tablets may contain the ac tive ingredient in admixture with conventional pharma ceutical cxcipients, c.g.. inert diluents such as calcium carbonate. sodium carbonate. lactose and talc. grand lining and disintegrating agents. eg. starch and alginic acid. binding agents. ee, starch. gelatin and acacia. and lubricating agents, ee. magnesium stearate. ste' uric acid and tale. The tahlets may he uneoated or coated by known techniques to delay disintegration and ahsorption in the gastrointestinal tract and theiehy provide a sustained action oyei a longer period Simi larly. suspensions. syrups and eli\irs may contain the acti\ e ingredient in admi\ture ith any ol the comen tional exeipients utili/ed for the preparation olsuch eoinpositions the. suspending agents 1 methylcellulose. tiagacanth and sodium alginate). wetting agents (leci thin. polyrnyethylenc stearate and polytnyethylene sorhitan monooleate) and pieseryatiyes (ethyl p hydroxyhenloate l, ('apsules prelerahly contain the ac the ingredient adini\ed with an inert diluent. up ealeium carhonate. calcium phosphate. kaolin or polyeth ylene glycolv lhe prelerred pharm:lceutieal eomposi tion lrom the standpoint of preparation and ease ol ad ministration are solid compositions. particularly tahlets and solid or liquid diluentl illed capsules.

RCIIILSLIllZIllVL lormulations for administration. I to 4 times a day. in treating inllammation are tablets and capsules prepared hy conventional techniques and containnn the following:

Ingredient X 31 ot 4.4'-diaeetylhiphenyl in It) ml. dry ethylenediaminc is added. After standing lb hours at room temperature. the mixture is poured onto ice and cflracted thriee with methylene chloride to yield crude 2-[4-(4 s aeetylhiphenylyll-5diniethylamino-B-pentynZ-ol.

Step ll .4 g of the product from Step A (without refining) is dissolved in ltltl ml. dry acetone. and subsequently treated with 5 ml. of dry iodoniethane. Alter standing l'or lh' hours at room temperature. the solution is concentrated. cooled aiid liltered to yield Z-l4-t-1'- acetylhiphenylyll-5 dimethylamino-3-pentynZ-ol methiodide.

Step H3 1 ol the product from Step B is suspended in 500 ml. dry diethylether. and 30 ml. ol'a l molar solution of lithium aluminum hydride in ether. is added at l'he mixture becomes clear. and the solution is then poured onto ice. The ether layer is sepa rated. dried quickly over anhydrous magnesium sulfate. and e\apol';ttcd to dryness. The residue is reerystallired lrom pentane diethyl ether (l:l l to yield 2-|4'-( lhydroxyethyll-hiphenylyllyll-J.4-pentadienZ-ol m.p. 7" to )S"('.

Repeating the procedure of this example. but replae ing the 4.4"diaeetylhiphenyl used therein with an ap proximately equivalent amount ol:

Weight in Milllpj'llllh lahlel ('apsule ('apsule T |l"( l hydrowcthyll lYIPlILIIYlrll St) t) tl .K-Lpentadicn lol liagaeanth lll lactose l 7 5 B (om Starch 15 lalcnm l Magnesium Steatale Y 5 Illll Polyethylene (ih'LHl (M W tulltltl) In the following esample which is illustrative ol the invention. temperatures are in degrees eentigrade. and room temperature is 20 to ,ltl(', unless indicated 0th crwise.

liXAMlll' O OH | CH CH T' 2 Step A ln Ztltl nil. l'reshly distilled ethylene diamine. l e olelean lithium wire is dissolved. After the l lue color has disappeared. 2,5 g of .l dimethylaminol'propy ne is added dropwise. at (1C, to the suspension. Alter the addition is completed. the mi\ture is allowed to stand at lll(. l'or 3 hours. alter which a solution of a. 4-aeetyl.4"t lhydroxyethyll-hiphenyl.

h. 44 lhydro\yelhyl )-4'-propionylhiphenyl. or

c. 4 l4-( l-hydroxyethyl)-phenyl I-henzaldehyde: there is similarly ohtained'.

a. ll 4'4 l-hydroxyethyl l-hiphenylyl |-3.4pentadienwherein R is a hydrogen atom. methyl or ethyl. 2. the compound otclaim I which is 2-l4'tlhydro\yetliyl l-hipheny'lyl l3 .-l-pentadien-Zol. 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 which is 2-(4''-(1-hydroxyethyl)-biphenylyl)-3,4-pentadien-2-ol. 